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Vol. 54, Issue 2, 323-374, June 2002

G Protein-Coupled Receptor Allosterism and Complexing

Arthur Christopoulos and Terry Kenakin

Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia (A.C.); and 7TM Pharmacology Systems Research, Glaxo Smith-Kline Research and Development, Research Triangle Park, North Carolina (T.K.)

I. Introduction
II. Allosteric Receptor Models of G Protein-Coupled Receptors
    A. Historical Perspective
        1. Cooperativity in Binding.
        2. Allosteric Transitions: Multistate Models of Receptor Action.
        3. Allosteric Interactions: Ternary Complex Models.
    B. Behavior of the Ternary Complex Model
    C. The Molecular Nature of Allosterism at G Protein-Coupled Receptors
        1. G Protein-Specific Receptor Conformations.
        2. Ligand-Specific Receptor Conformations.
III. Detecting Allosteric Interactions
    A. Assays of Radioligand Binding
        1. Equilibrium Binding Assays.
        2. Inhibition Binding Assays.
        3. Nonequilibrium (Kinetic) Studies.
    B. Assays of Receptor Function
        1. Schild Analysis.
        2. Additivity of Concentration Ratios.
        3. Pharmacological Resultant Analysis.
    C. Potential Pitfalls
IV. Usefulness of Allosteric Modulators
V. Location of the Allosteric Site(s)
    A. Locks and Keys
    B. Modulation by Ions
    C. Interactions at the Receptor-G Protein Interface
    D. Extracellular Allosteric Sites
        1. Multiple Allosteric Sites.
VI. Endogenous Allosteric Modulators
VII. G Protein-Coupled Receptor Complexing
    A. Receptor-Receptor Interactions
    B. Accessory Proteins
VIII. Conclusions
Acknowledgments
References

G protein-coupled receptors (GPCRs) represent the largest family of cell-surface receptors. These receptors are natural allosteric proteins because agonist-mediated signaling by GPCRs requires a conformational change in the receptor protein transmitted between two topographically distinct binding sites, one for the agonist and another for the G protein. It is now becoming increasingly recognized, however, that the agonist-bound GPCR can also form ternary complexes with other ligands or "accessory" proteins and display altered binding and/or signaling properties in relation to the binary agonist-receptor complex. Allosteric sites on GPCRs represent novel drug targets because allosteric modulators possess a number of theoretical advantages over classic orthosteric ligands, such as a ceiling level to the allosteric effect and a potential for greater GPCR subtype-selectivity. Because of the noncompetitive nature of allosteric phenomena, the detection and quantification of such effects often relies on a combination of equilibrium binding, nonequilibrium kinetic, and functional signaling assays. This review discusses the development and properties of allosteric receptor models for GPCRs and the detection and quantification of allosteric effects. Moreover, we provide an overview of the current knowledge regarding the location of possible allosteric sites on GPCRs and candidate endogenous allosteric modulators. Finally, we discuss the potential for allosteric effects arising from the formation of GPCR oligomers or GPCRs complexed with accessory cellular proteins. It is proposed that the study of allosteric phenomena will become of progressively greater import to the drug discovery process due to the advent of newer and more sensitive GPCR screening technologies.

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PHARMACOLOGICAL REVIEWS
Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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